Sara Tiner (@saratiner)

A report by Mayo researchers adds a new wrinkle to the diagnosis of lymphoid malignancies. The case report in the Journal of Allergy and Clinical Immunology is focused on one patient and protein used by the immune system, called an antibody.

Antibodies are Y-shaped proteins produced by a sub-group of white blood cells called B lymphocytes. They flood the blood, stick to their target (bacteria, viruses), marking them for “clean up” by other cells of the immune system. The Y-shape has two components: light chains and heavy chains. Together, the light and heavy chains make the two arms of the Y, whereas the base is only made by the heavy chain.

“The study describes a patient who lacks the kappa light chain, the main form of light chain in human antibodies,” explain Amir A. Sadighi Akha, M.D., D.Phil. and Maria A. V. Willrich, Ph.D. The two are immunologists at Mayo and corresponding authors of the paper. “This was a chance finding in the patient’s serum, and prompted the more specialized tests performed afterwards.”

Left to Right: Dr. Sadighi Akha and Dr. Willrich. Their work on complete kappa light chain absence is published in the Journal of Allergy and Clinical Immunology.

The absence of the kappa light chain does not increase the risk of infection, but it can lead to abnormal lab findings. The most important of these is the possibility of diagnosing a patient with B lymphocyte cancer by mistake.

“So far, only 3 patients with kappa light chain absence, including ours, have been reported in the world, but recent estimates suggest that at least 300 people in the United States could have this condition”, say the authors. “Therefore, pathologists should have this condition in mind when evaluating a patient for B lymphocyte disorders.”

Going forward, the authors will work on making
physicians aware of this diagnostic possibility in patients being evaluated for
B lymphocyte disorders.

No funding entities supported this work. The authors disclose one conflict of interest: David Murray, John Mills, and Surendra Dasari have intellectual property and receive royalties related to the analysis of immunoglobulins by mass spectrometry.

According to a new paper in Nature Communications, a protein known to help cells defend against infection also helps their mitochondria. The protein, one in a group called myxovirus-resistance (Mx) protein, helps cells without calling in white blood cells. But now, the researchers report it also helps cells by preventing a virus from hijacking mitochondria.

“Our work provides new insights into how this protein assists in fighting viral infections, which could have substantial health implications in the future,” says senior author Mark McNiven, Ph.D., a cell biologist at Mayo Clinic.

This basic science
finding expands understanding of the innate immune response. It is an example
of how discovery research at Mayo helps identify targets for future clinical
investigation.

When infected, a
cell sends out a chemical alarm called interferon. In response, neighboring
cells ramp up production of Mx proteins. These proteins block entry into the
nucleus, preventing a virus genome from replicating. They also bind to viral
genomes and disrupt replication.

The authors of the
new paper looked at immune tissues, such as tonsils, for the presence of one
myxovirus protein called MxB. They found some MxB in most cell types tested.
They also found that it increases when cells are treated with interferon. As
others have reported, the Mayo team also found that MxB moved to the nucleus
during the “red alert.”

However, they found
MxB did something else, as well.

“We were surprised to see MxB present on and in mitochondria,” says first author Hong Cao, M.D., a research scientist at Mayo. “That it is both induced in response to infection and vital to mitochondrial integrity is exciting, considering the two viruses MxB mitigates, HIV and herpes, alter mitochondria during infection.”

Protecting the Generator

Mitochondria are specialized
structures in cells, called organelles. They produce energy and are vital to
cellular health. Existing by the hundreds in each cell, their outer shape can
change. What doesn’t change is that inside, mitochondria have folds of tissue,
called cristae. These folds are where the energy generation process takes
place.

During infection MxB
condenses, dissolves, and reforms over time. It travels in the cell — to the
nuclear pores, but also along mitochondria or at their tips. But to see what
MxB does there, the researchers had to use cells that were prevented from
making MxB. What they found provided a new role for the protein.

“Without active MxB,
mitochondria become nonfunctional and kick out their DNA into the cytoplasm,”
explains Dr. Cao. “These cells are not happy but may have the capacity to
survive a viral infection.”

The image at left shows normal cells with tubular mitochondria (red), and DNA (green) in the nucleus and within the mitochondria. At right, MxB has been removed by genetic means and leaves fragmented mitochondria (red) with its genome displaced into the cytoplasm.

History of Mitochondrial Investigation

The work of Dr. Cao
and team builds on the findings of a solid cadre of mitochondrial investigators
at Mayo.

“Over two decades
ago our lab discovered a set of proteins that perform mechanical work to shape
and pinch mitochondria,” says Dr. McNiven.
That discovery led to a variety of research initiatives across the
international mitochondria field into not only basic research questions, but also
into clinical areas. This work has established that mitochondrial changes
regulate cell death, which is important for diseases such as cancer and
neurodegenerative disorders, and in antiviral cell immunity.

The next steps, Dr.
McNiven says, are for his team to investigate how MxB gets to and into
mitochondria. They will also examine how its association causes changes to this
organelle.

In addition to Drs. Cao and
McNiven, other authors on the paper ― all from Mayo Clinic at the time of
publication ― are Eugene Krueger, Jing Chen, Kristina Drizyte-Miller in the
Mayo Clinic School of Graduate Education and Mary Schulz.

Funding was provided by federal
entities and through Mayo Clinic Center for Cell Signaling in Gastroenterology.
Detailed information is in the publication, Nature Communications.

Breakthroughs in medical science rarely burst on the scene. Behind every advance is years of work by dogged researchers who nurtured the seed of idea until it flowered, bore fruit and materialized into a better treatment, device or therapy for patients. Here is where those seeds start: More than a dozen projects related to cancer, cell structures, genetics and epigenetics, immunology and tissue regeneration were funded in this year’s Mayo Clinic Center for Biomedical Discovery 2019 Pilot Grants. The award provides focused, one-time funds for imaginative proof-of-principle studies or model-development needed to lay the foundation for future efforts.

Osteoporosis

Bone marrow fat (adiposity) is a hallmark of aging bones. Rising levels are correlated with reduction in bone density, which can lead to osteoporosis. Jennifer Westendorf, Ph.D., and team will clarify the role of adipose tissue in bone marrow and discover the pathways that encourage this yellow marrow to form. They will examine the composition of the marrow adipose tissue and a genetic regulator, called histone deacetylase 3, for its role in changing gene expression and cellular composition of bone marrow.

Cellular Antennae and a Rare
Disease

With this new funding, Haitao Wang, Ph.D., and Jinghua Hu, Ph.D., will investigate how a cellular “antenna,” or cilium, determine how stem cells differentiate into muscle, connective tissue, or bones. The knowledge will help us to understand many degeneration diseases that currently have no treatment or cure.

Inflammatory
Bowel Disease

This team will investigate the interaction between cellular metabolism and intestinal macrophage functions. They are investigating what role, if any, this interaction plays in controlling gut inflammation as seen in inflammatory bowel disease. Study investigator W K Eddie Ip, Ph.D., hopes to use this work to further understand how inflammatory bowel disease begins and what therapeutic targets might be on the horizon.

Fibrosis

Fibrosis is a serious disease process characterized by uncontrolled internal scarring. Researchers Daniel Tschumperlin, Ph.D., Christopher Evans, Ph.D., and Robert Vassallo, M.D., are hoping to better understand the biology of fibrosis and how loss of important transcription factors affects the disease process. The team will investigate the transcription factor CEBPA and develop a new approach to enhancing its expression in lung epithelial cells to reduce fibrosis.

In cell and mouse models, Mayo Clinic researchers and collaborators have identified a way to slow and reverse the process of uncontrolled internal scarring, called fibrosis. The findings were published in Science Translational Medicine.

Liver Regeneration

The researchers on this project are looking at how the liver heals after injury. They hope this knowledge will improve how patients undergoing surgery of the liver recover, and provide ideas on how to support liver regeneration. The researchers on this project are Rory Smoot, M.D., Patrick Starlinger, M.D., Ph.D., and Gregory Gores, M.D. They report that preliminary data suggests a role for the Yes-associated protein (YAP) and will explore if SHP2 inhibition increases YAP activation in a mouse model and if increased YAP activity results in accelerated liver regeneration in a mouse model.

Mayo Clinic researchers are pursuing a range of investigative approaches to better understand and predict the impact of mitochondrial malfunctions, with the goal of helping patients. Read more at Discovery’s Edge.

Cancer, Cancer Treatment and Cancer
Treatment Side-Effects

One cancer-related effort will examine cytotoxic T lymphocytes and their role in immunotherapy. Two projects were funded in this area. One will investigate a protein called NKG7, identified by the research team as being associated with a lack of benefit in immunotherapy. Led by Haidong Dong, M.D., Ph.D., and Daniel Billadeau, Ph.D., the team will develop antibodies to detect NKG7 in patient samples and generate cell lines without the genetic ability to produce NKG7. In a second project, Dr. Dong, Roxana Dronca, M.D., and Yiyi Yan, Ph.D., will create a mouse model to examine the role of NKG7 in the ability of CD8-positive T cells to respond during anti-programmed death ligand 1(PD-L1) therapy. The researchers hope that by clarifying the role of mediators to cytotoxicity, they can improve patient response to PD-1 checkpoint blockade immunotherapy.

Also
related to immunotherapy, a pilot grant was awarded to Frank
Sinicrope, M.D., and Bo Qin, Ph.D., to study the association of the immune
checkpoint protein PD-L1 with a cell-death regulator called BIM in colorectal
cancer cells. They will examine if PD-L1 controls the level of BIM protein via
an enzyme known as an E3 ligase.

Funding
was also provided to establish a mouse model that will examine long noncoding
RNA. The researcher leading the project, Wenqian
Hu, Ph.D., and his team report that these RNA are important during the
production of red blood cells and regulation of the stem cells that develop
into blood cells. The team will focus on a specific RNA, called Dleu2, and hope
that the mouse model will reveal how it regulates normal blood cell formation
as well as novel insights into the development of chronic lymphocytic leukemia.

To read more about how advances in lab models will ultimately help the medical treatments, read Mimicking Cancer at Discovery’s Edge.

In another project aimed at blood stem cells, researchers will look at the possibility of predicting the evolutionally trajectories from normal to acute myeloid leukemia and myelodysplastic syndromes, based on variants of a germline zinc finger transcription factor called GATA2. This factor is critical in formation of the stem cells that develop into blood cells. This project will be undertaken by Mrinal Patnaik, M.B.B.S.; Ryan Carr, M.D., Ph.D.; Terra Lasho, Ph.D.; and Moritz Binder, M.D.

A
pilot grant to examine chemotherapy-induced
nerve damage was awarded to Christopher Groen, Ph.D., Jewel Podratz, and Anthony
Windebank, M.D. In a Drosophila model,
the researchers have identified genetic variations in mitochondria genes that
provide resistance to neuropathy (read about their work in Discovery’s
Edge). The award will allow them to examine changes in mitochondria
that confer that resistance novel 3D electron microscopy available through the
Microscopy and Cell Analysis Core Facility. If successful, their work has the
potential to establish a direct link between mitochondrial health and
chemotherapy-induced peripheral neuropathy outcomes.

To study the inherent genetic instability of cancers, a grant was awarded to Larry Pease, Ph.D., and Keith Robertson, Ph.D., who will focus on genetic markers in breast cancer. In their work to date, they’ve detected a form of genetic instability that pervades the genome of breast cancer cells and allows tumors to evade homeostatic cell growth regulation and tumor recognition by the immune system. To look into the nature of genetic changes allowing tumor evolution, the researchers will develop a mouse model of spontaneous breast cancer that can be targeted specifically by tumor suppressing immune cells, enriching for locus-specific modifications in HER2 gene expression in tumor cells escaping from tumoricidal immune attack.

T-cells are having a moment. Well maybe not like Game of Thrones is having a moment, but as stars of the cancer treatment, immunotherapy, T-cells are definitely cool. But what is a T-cell? And how can you get one?

Good news! Your body makes T-cells for you, a lot of them.
All the time.

Wannabe T-cells are born
in bone marrow and migrate to the butterfly-shaped organ called the thymus. Put
your hand on your neck, right where the collar bones meet. There, now you’re
almost touching your thymus, which is in your rib
cage just above your heart. A butterfly is a good metaphor to keep in
mind, too. Like an egg becomes a caterpillar that becomes a pupa which becomes
a butterfly, the T-cell goes through a life cycle to become the powerhouse
protector of the body. As part of that cycle, T-cells in the thymus learn if
they have aptitude for one of two jobs. But the thymus is less job training and
more Hunger Games. The majority never make it out because the body culls any
that aren’t just right.

Red Alert / Chemical
Weapon

The overall task of a T-cell is to respond to markers, called antigens, left behind by invaders, which stick to cells in our body. T-cells have a port, or receptor, that matches to an antigen. When that happens, the T-cell turns into either a chemical weapon or an alarm bell.

Both are vital, according to Virginia Shapiro, Ph.D., immunologist and co-lead for the immunity platform for Mayo Clinic’s Center for Biomedical Discovery.

Virginia Shapiro, Ph.D.

“One type of T-cell can recognize that the danger is
coming from inside a cell, as in the case of a virus, and will inject it with a
granule of toxic chemicals. Those are the cytotoxic (kills living cells)
T-cells or CD8 T-cells,” she explains. The other type is the CD4, or
helper T-cell, Dr. Shapiro continues. “These are the cells that get the
immune message, become activated, but do not kill the messenger.”

Sometimes T-cells can take care of the problem then and
there, but other times, the immune system needs to coordinate for a larger
clean-up mission. So both types of T-cells are important for a robust immune
response.

But remember: ALL THE THINGS. How can your body create T-cells
with receptors for all the antigens it might encounter?

“How many protein-coding
genes are there in people?” asks Dr. Shapiro. “Twenty-one thousand-ish,” she says, answering her
own question. “But the body has to make antigen receptors to, well, let’s
just say a gazillion things for simplicity.” She explains that the way
that happens is the body takes gene segments, mixes and matches them in a way
that’s, “actually a bit sloppy but that increases diversity even more.”

And what you get is a T-cell with a receptor but no idea
what it might recognize.

“Two thirds of the rearrangements will produce
junk,” says Dr. Shapiro. “So part of the process is to go through
quality control checkpoints so you only keep T-cells with receptors that are
good.” In the thymus, immature T cells are tested. If the response from
the receptor array (signal) does not react to anything, they’re told to die. If
their receptor reacts to the part of the cell that defines “you” (versus
“not-you”) then they’re also culled to prevent damage to your own
tissue.

“You need the signal through the receptor to be not too
strong, not too weak but just right,” says Dr. Shapiro. “Once it’s in
that goldilocks zone, the T-cell has a choice. Do I become a helper T-cell or a
cytotoxic T-cell?”

Providing a Choice

In a recent paper in eLife, Dr. Shapiro and her team clarified an important part of this process in mice. At the point where surviving T-cells choose what to be, an enzyme called histone deacetylase 3 or HDAC3 helps keep both options open. It is part of a family of enzymes that typically repress gene expression. In this case Dr. Shapiro’s team reports that HDAC3 holds back the expression of genes that push a T-cell to become cytotoxic and allow T-cells down the path of becoming helper cells.

“When it comes to making that decision T-cells have two
fates,” says Dr. Shapiro. “But when HDAC3 is gone, it doesn’t matter
if you were supposed to be a cytotoxic or a helper. The deck is stacked and everybody
becomes cytotoxic.”

That means only T-cell chemical weapons, no T-cell alarms to
coordinate immune response.

In a separate paper, published in The Journal of Immunology, the team expanded on the role of HDAC3. They report that it also suppresses genes for a particular receptor called P2X7.

“P2X7 is a receptor that recognizes the energy molecule
in cells, which they release as they die,” explains Dr. Shapiro.
“With only 10 percent of T-cells in the goldilocks zone, there are lots of
dying cells, meaning the thymus is an environment rich in that molecule, called
ATP. So without HDAC3, you have more P2X7 receptor
expressed on the surface of the T-cells and more cell death, meaning fewer
T-cells in general.”

That means without HDAC3, the body can only produce chemical
weapons and will produce fewer T-cells in general.

And that could be a problem for patients during cancer
treatment.

T-Cell Development
Informs Cancer Therapies

Some cancer treatments use HDAC-inhibitors. That is, as part
of treatment they block HDAC. Now, if you already have helper T-cells you don’t
need HDAC3.

“But tumors are really good at shutting down an immune
response and exhausting T-cells,” says Dr. Shapiro. “You depend on
having newly generated T-cells coming into the tumor that have not been spoiled
by the tumor. So these inhibitors may have an effect on normal cells and
introduce unintended effects.”

Right now, Dr. Shapiro says, we have the broad picture and
we know HDAC3 is critical, but “the next step is to understand it at a
mechanistic level and ask the molecular questions.”

To improve cancer therapy, we have to understand one of the
body’s best weapons against it, says Dr. Shapiro.

“If you have diseases which disrupt the ability to make
T-cells it has a severe effect on health,” Dr. Shapiro says. “So at the
most basic level we care about how you make a T-cell.”

This disease is cancer of an immune cell called a B lymphocyte. These cells form in bone marrow and migrate out to patrol in the blood stream and lymphoid organs. But in chronic lymphocytic leukemia, the immune system is depleted, a state called immunodeficiency. Because of that, people with this type of leukemia are prone to serious infections and the diseases those may cause. They are also prone to developing other types of cancer.

And it’s those resulting problems that may ultimately contribute to death explains Kay Medina, Ph.D., a Mayo Clinic immunologist. Dr. Medina specializes in how immune cells develop from bone marrow stem cells.

In our bone marrow, stem cells convert to red blood cells, platelets or a variety of immune cells. Those are then sent into the blood stream where they do their job. Red blood cells replace cells that are worn out.

White blood cells patrol the byways of our circulation, chasing down everything from cellular debris to bacteria to virus particles. But not in patients with chronic lymphocytic leukemia.

Joining the Team

Research on chronic lymphocytic leukemia is going on in several labs at Mayo Clinic. Dr. Medina got involved after speaking with colleagues Wei Ding, M.B.B.S, Ph.D., and Neil Kay, M.D., both chronic lymphocytic leukemia physician researchers.

“Mayo has a strong tradition of encouraging physician/basic research collaborations to advance knowledge of disease mechanisms, development, and assessment of new treatment approaches,” says Dr. Medina.

The basic research helps us understand the cause of the disease, in this case the leukemia cell, but it also helps to understand what the disease does to other parts of the body, such as the lymph nodes, spleen, blood and bone marrow, she says.

“Bone marrow is the organ that replenishes all cells in the immune system but has not been evaluated for functional proficiency in CLL patients,” explains Dr. Medina.

Checking out the Cells and their Environment

Kay Medina, Ph.D.

Dr. Medina’s team, with funding from Mayo Clinic’s Center for Biomedical Discovery, decided to look at bone marrow stem cells and their ability to generate all blood cell types. Some of the immune deficiency may be the result of treatment, but untreated patients have the same problem. The chronic nature of the disease itself may also dampen immune activity. But Dr. Medina explains that the leukemia cells may promote an environment that suppresses immune function.

“Our research seeks to add to the discussion by identifying additional ways patients with CLL are unable to fight off tumors and other diseases,” says Dr. Medina.

In a paper published late last year, Dr. Medina and her team, including first author Bryce Manso who is a student in the Mayo Clinic Graduate School of Biomedical Sciences, examined bone marrow and blood samples from chronic lymphocytic leukemia patients and healthy controls to determine the frequency of bone marrow stem cells in each sample and how well they did their job.

Bryce Manso, presenting a poster to a conference attendee.

The authors reported that, in general, samples from patients with chronic lymphocytic leukemia have fewer stem cells in their bone marrow, and those stem cells that remain work less well than stem cells from controls.

Stalled-Out Bone Marrow Stem Cells

As to why this happens, the authors found that it was linked to loosening controls for the on/off switches which regulate this process, proteins called transcription factors. These proteins regulate key functions in the cell, and are out of whack in samples from chronic lymphocytic leukemia patients. They may prevent bone marrow stem cells from pursuing a pathway for development; stalling-out their ability to differentiate, resulting in decreased production of important blood cells that provide the first line of defense against infectious agents.

But, Dr. Medina cautions, there is more to this story.

“This is an emerging area of research in that it’s both a unique explanation for the clinical problem of immune deficiency and it has been minimally studied,” says Dr. Medina. “Future studies are planned to look at specific transcription factors that control stem cell differentiation as well as how the presence of leukemic cells in the bone marrow alter blood cell development.” They will then relate this information to clinically relevant complications reported in chronic lymphocytic leukemia patients, she says.

Basic Research to Improve Patient Care

Dr. Medina, her team, and their clinical colleagues hope that by understanding how bone marrow function is impaired in chronic lymphocytic leukemia patients, they can develop unique strategies to boost bone marrow function or find alternate treatments that do not block or modify marrow function.

“Through this work we hope to find ways to reduce infections and the incidence of second cancers in chronic lymphocytic leukemia patients. Our research has the potential to improve quality of life as well as extend the lives of these patients” says Dr. Medina.

Medical breakthroughs start in the lab with a phase of research called discovery science. It helps to understand how the body functions and how disease begins at the most basic level. That in turn provides insight into how whatever has gone wrong can be fixed.

To kick off the medical treatments of tomorrow, the Center for Biomedical Discovery is proud to support the following Discovery Science Award projects for 2019. These projects all promote innovative, cutting-edge discovery science teams that focus on understand the biological processes that contribute to human disease.

Investigating the role of a Gene in how a normal immune process goes bad

When we encounter infectious agents – either naturally or by vaccination – our immune system generates a highly selective defense against that particular danger. While essential for healthy life, this ability comes at a price: lymphomas. These cancers arise when immune cells edit their genetic material to customize and optimize the reaction to infections. Our work will uncover how the gene UCHL1 regulates the building of proteins in normal and cancerous immune cells in hopes of gaining a better understanding of how we might harness these events to enhance immunity – and fight cancer.

Can a form of cellular communication hamstring the newest immunotherapy treatment?

This project will investigate the idea that small particles, called extracellular vesicles, produced by chronic lymphocytic leukemia B cells and secreted into the circulation can bind to chimeric antigen receptor T-cells (CAR T-cells) and blunt their ability to recognize tumor cells. We have identified a specific receptor on the extracellular vesicles as the trigger signal responsible for this impairment of function. This may unveil a unique functional role of leukemic extracellular vesicles. It is also meaningful to see if this mechanism is applicable to other disease states where we know that CAR T-cells also do not work, including solid tumors.

Studying colon cancer to clarify metastasis and identify new treatments

Using patient-derived tumors grown in 3-D vessels (organoids) and artificial intelligence-based approaches we will: Identify potential targets for colon cancer therapy, improve understanding of what causes tumor metastasis, detect patients with tumors at high risk of progression, and identify new treatment methods targeted at slowing or halting tumor progression. We will characterize how a protein associated with epigenetic processes in cells, HP1α, alters cell signaling in colon cancer. We will also characterize how loss of HP1α impacts mitotic fidelity in colon cancer, and we will identify targetable changes in tumor cells caused by disruption of HP1α.

Although obesity is a risk factor for type 2 diabetes mellitus, most people who are obese do not develop diabetes. Their β-cells are able to increase insulin output and maintain normal blood glucose. However, in a subset of people β-cells fail leading to development of the disease. Our group will test whether increased expression of a specific gene/protein (SLC4A4/NBCe1) is the main culprit in leading to failure of β-cells to produce enough insulin in type 2 diabetes mellitus. The ultimate goal of these studies is to provide novel information into how the disease develops, and identify novel therapeutic strategies to treat/prevent this disease.

We are testing the hypothesis that prematurity and high oxygen suppress hydrogen sulfide expression and function in the airway, thus blunting the beneficial effects of the gas. We will use cell and mouse models of asthma exposed to moderate hyperoxia and test the efficacy of hydrogen sulfide gas we well as novel hydrogen sulfide donors in inducing bronchodilation and preventing cell proliferation and fibrosis. The results of these novel studies will provide significant insight into the mechanisms of hydrogen sulfide generation and action in developing airways, and conversely the benefit of using the gas as a therapeutic target to treat airway diseases in premature babies.

The humoral immunity is essential but abnormal B cell activation contributes to autoimmune disorders, including systemic lupus erythematosus, which has no cure and lack new effective treatment. Our preliminary results show that B-cell function relies on fatty acid synthesis mediated by an enzyme, stearoyl-CoA deasaturase. Inhibition of that enzyme alleviates disease pathology in a mouse model of systemic lupus erythematosus. This proposal aims to investigate how stearoyl-CoA deasaturase-mediated fatty acid metabolism modulates B-cell differentiation and autoimmune diseases. We will also examine whether this mechanism is involved in human autoimmune diseases.

With this model, Mayo has made progress in studies that use electrical stimulation to address paralysis and investigate stem cells for use in medical care. It supports the NIH All of Us Research Program aimed at advancing individualized care, helps understand disease where it starts at the level of the cell, and examine the role of senescent cells in aging and diseases of aging.

If you are a human who ages, or one who would like to see better treatments for disease, consider adding the Mayo Model of Research to your gift list today.

It’s an easy one to give: Tell someone you love how research at Mayo is helping save lives, or share stories about Mayo Clinic research that you find on this blog, Discovery’s Edge or other Mayo Clinic sources like Facebook or Twitter. That’s it. A share here, a retweet there and you’re done.

It could help someone in your social network now, and it will help patients in the future.

The right diet, obesity and gut health are topics patients, clinicians and scientists wrestle with every day. We want to eat a good diet and lose weight or avoid weight gain, so our health span matches our life span.

But statistics suggest we struggle.

To help, scientists are examining how food, our gut, and our weight are related. Purna Kashyap, M.B.B.S. moderated a break out session on personalized nutrition at the Individualizing Medicine Conference 2018, during which those examinations led to three conclusions that may change the way we look at our food, our gut and our weight loss plans:

The environment inside our gut is governed by the same rules as the environment outside the body.
The rules that ecologists have discovered in the natural world hold sway in our gut, too. According to Jens Walter, Ph.D., of the University of Alberta in Canada, while our gut microbes can change, the pattern of change is predictable. For example, where microbes roam (dispersal) and how they win their territory (selection) in the gut, follow the same rules as seeds dispersing from a plant or two seed-eating birds competing for a common food source. This knowledge can help researchers cut through the variation between individuals to understand the underlying similarities in our gut ecosystem.

Yo-Yo dieting may be due to a memory of famine in our gut microbes.
While science often examines what leads to obesity, patients are often already there. We typically need to lose weight and keep it off for health reasons. But keeping weight off is difficult and researcher Christoph Thaiss, Ph.D., of the University of Pennsylvania wanted to know why. In a series of mouse experiments he and his team replicated yo-yo dieting and discovered that the microbiome remembers feast and famine, and adjusts accordingly. After weight loss, when mice were given a high-fat diet, they regained more weight faster than they had in the first round of weight gain.

The researchers then delved into the specifics of what changed in a post-obesity mouse gut and identified two molecules that were lost: apigenin and naringenin. These plant-derived flavonoids are associated with the tendency to maintain a low weight over time, says Dr. Thaiss, and when mice were supplemented with both in their diet, the mice were able to “forget” the period of obesity and avoid regaining weight. Dr. Thaiss explained that one theory is that this mechanism might be an evolutionary response to fluctuating environmental conditions. In forthcoming research, Dr. Thaiss is examining this effect in humans.

Eating food your gut microbes want can help keep blood glucose levels stable.
Humans have been in pursuit of the best diet ever since we had a choice in the matter. But despite a long and vigorous effort, the best diet eludes researchers, said Tali Raveh-Sadka, Ph.D., director of research at DayTwo. The company is one of a few new ventures that gather data from consumers, digest it in a computer algorithm, and report back personalized food recommendations.

When participants in one trial were fitted with a continuous glucose monitor, the variety of responses was high. One person’s blood sugar spiked when consuming a banana but not a cookie, explained Dr. Raveh-Sadka, but another participant had the opposite response. The researchers found that when participants ate the “good for their microbiome” diet, their microbiome shifted and their blood sugar readings remained stable.